期刊
PHARMACEUTICS
卷 14, 期 10, 页码 -出版社
MDPI
DOI: 10.3390/pharmaceutics14102200
关键词
Alzheimer's disease; transferrin receptor; TNF-alpha inhibitor; blood-brain barrier; molecular Trojan horse
资金
- National Institute of Aging of the National Institutes of Health [R01AG062840, R01AG072896]
TNF-alpha inhibitors play a crucial role in the pathology of Alzheimer's disease, and delivering them to the brain can enhance their therapeutic effects. In this study, the fusion of TNF-alpha receptor with a transferrin receptor antibody showed better therapeutic outcomes in aged APP/PS1 mice compared to other TNF-alpha inhibitors, without causing any hematological or iron-related dysregulation.
Tumor necrosis factor alpha (TNF-alpha) plays a vital role in Alzheimer's disease (AD) pathology, and TNF-alpha inhibitors (TNFIs) modulate AD pathology. We fused the TNF-alpha receptor (TNFR), a biologic TNFI that sequesters TNF-alpha, to a transferrin receptor antibody (TfRMAb) to deliver the TNFI into the brain across the blood-brain barrier (BBB). TfRMAb-TNFR was protective in 6-month-old transgenic APP/PS1 mice in our previous work. However, the effects and safety following delayed chronic TfRMAb-TNFR treatment are unknown. Herein, we initiated the treatment when the male APP/PS1 mice were 10.7 months old (delayed treatment). Mice were injected intraperitoneally with saline, TfRMAb-TNFR, etanercept (non-BBB-penetrating TNFI), or TfRMAb for ten weeks. Biologic TNFIs did not alter hematology indices or tissue iron homeostasis; however, TfRMAb altered hematology indices, increased splenic iron transporter expression, and increased spleen and liver iron. TfRMAb-TNFR and etanercept reduced brain insoluble-amyloid beta (A beta) 1-42, soluble-oligomeric A beta, and microgliosis; however, only TfRMAb-TNFR reduced A beta peptides, Thioflavin-S-positive A beta plaques, and insoluble-oligomeric A beta and increased plaque-associated phagocytic microglia. Accordingly, TfRMAb-TNFR improved spatial reference memory and increased BBB-tight junction protein expression, whereas etanercept did not. Overall, despite delayed treatment, TfRMAb-TNFR resulted in a better therapeutic response than etanercept without any TfRMAb-related hematologyor iron-dysregulation in aged APP/PS1 mice.
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